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Mycobacterium tuberculosis host adaptation and evolution reflected by defense mechanisms against oxidative stress

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Resumo:Part of the success of Mycobacterium tuberculosis lies in its ability to thrive inside macrophages, where it is exposed to strong antimicrobials molecules, such as reactive oxygen species (ROS). However, the role of defense mechanisms against ROS in M. tuberculosis pathogenesis remains unclear. We used, for the first time, a functional genomic approach to investigate M. tuberculosis responses against ROS. By screening a transposon mutant library we identified a high number of mutants, with increased susceptibility to H2O2, in genes related to cell envelope functions, including mmpL9. This revealed the importance of M. tuberculosis cell envelope against oxidative stress. However, we have also identified genes implicated in other kind of defense mechanism against ROS, such as moaD1. Infection of human macrophages has shown that both mmpL9 and moaD1 have a role in M. tuberculosis intracellular lifestyle, and previous studies suggested the same for several other genes identified during our screening. Therefore, these represent potential virulence factors useful for the development of future anti-tuberculosis strategies. DNA repair, recombination and replication (3R) are important mechanisms in maintaining genome stability by repairing DNA damages, such as those induced by ROS, however, variations on 3R genes potentially increase genomic variability, due to an increase in mutation rates. Thus, analysis of polymorphisms in 3R genes could indicate which strains are more prone to adapt and evolve. We have analyzed polymorphisms in 3R genes in a collection of strains of a successful family of M. tuberculosis strains, the Beijing/W family. Specific 3R polymorphisms were found to characterize particular groups of Beijing/W strains for which a phylogeny was constructed. Certain groups were found to be predominant, suggesting that strains of these genotypes might have some selective advantage. Therefore, particular 3R SNPs may define pathogenic features that have contributed to the evolution of the Beijing/W family.
Autores principais:Mestre, Olga Maria Elviro, 1984-
Assunto:Teses de doutoramento - 2012
Ano:2012
País:Portugal
Tipo de documento:tese de doutoramento
Tipo de acesso:acesso aberto
Instituição associada:Universidade de Lisboa
Idioma:inglês
Origem:Repositório da Universidade de Lisboa

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